According to the classical view, atherosclerosis is a condition ultimately leading to the narrowing of blood vessels, impaired circulation, and restricted oxygenation of tissues (1). If this process occurs in heart vessels (coronary arteries), consequences are the clinical conditions of angina pectoris and myocardial infarction; in the brain, atherosclerosis leads to cerebrovascular accidents; in the legs, the clinical presentation is claudicatio intermittens. Classical risk factors Associated with atherosclerosis are: obesity, hypertension, smoking, diabetes, male gender, fasting hyperlipidemia, and especially increased cholesterol concentrations. Novel risk factors have emerged during the last decennia, these including hyperhomocysteinemia, hypertriglyceridemia with low HDL cholesterol concentrations, postprandial hyperlipidemia, the insulin resistance syndrome, and a positive family history for cardiovascular disease, among others.
According to epidemiological surveys, coronary heart disease (CHD) is the leading cause of death in western societies. In the United Kingdom in 1987, 31% of all deaths in males (280.177 total deaths in men) and 24% in females (total number: 286.817) were due to CHD. More than one quarter of CHD deaths in men (total CHD mortality in men: 86.978) occurred before the age of 65 years. In women (68.257 CHD deaths), the vast majority (almost 75%) occurred at ages beyond 75 years. The Dutch situation is similar and representative for other countries in Western society. In The Netherlands in 1997, there were 135.783 deaths in total (67.242 males and 68.541 females). In men, 37% of total mortality (24.664 deaths) was due to CHD and in women 38% (25.881 deaths). From 1972 to 1997, mortality due to CHD in The Netherlands decreased by 44% (age-corrected); however, hospital admissions related to CHD increased by 53%. This decrease in CHD-associated mortality is probably ascribed to improved care in coronary-care and intensive-care units. In addition, the early recognition of the above-mentioned risk factors for CHD and improved treatment of these risk factors may have led to increased survival in patients at risk.
The classical drugs for the treatment of these risk factors are cholesterol-lowering drugs (mainly statins) (3), drugs aiming at the reduction of blood pressure like angiotensin-converting-enzyme inhibitors (4) and drugs like aspirin which act on clot formation. The effects of life-style change to reduce body weight and stopping smoking have been disappointing so far, although their impact has not been established adequately on a population basis. Improvement of regulation of diabetes has resulted in decreased morbidity (less amputations, less diabetics with end-stage renal failure necessitating dialysis, and less diabetics becoming blind) (5, 6), but the incidence of cardiovascular disease in diabetics did not decrease by these measures (6, 7).
Many investigators point at the need for the recognition of concealed risk factors for CHD in diabetes (and obesity) and a more aggressive treatment of these factors should result in improved outcome. Moreover, land-mark trials with lipid-lowering drugs in secondary and primary prevention settings have resulted in significantly decreased mortality in treated patients (30% risk reduction) (2), but there were still significant numbers of patients that could not be saved by these drugs. Therefore, the identification of additional risk factors and the development of novel therapeutic interventions are expected to result in a significant reduction of total mortality due to CHD.
It has been postulated that atherosclerosis is associated with an impaired clearance of chylomicron remnants, i.e., partially hydrolyzed chylomicrons (intestinally-derived triglyceride-rich lipoproteins). Also, it was suggested (PCT International Patent Publication WO 00 34469) that clusterin could be used as a migration inhibitor of vascular smooth muscle cells in arteries whose migration and proliferation may lead to vessel injury and arterial lesion and whose migration and proliferation can be induced by atherosclerosis. Rosenberg and Silkensen (10), in reviewing the multifunctional protein role of clusterin state the determination of a common mechanism underlying its various functions would lead to a key in comprehending an important area of biology. Other researchers (11) have demonstrated that clusterin (apo J) may have a protective role against atherosclerosis as it participates in cholesterol transport.
One of the recently recognized mechanisms in the development of atherosclerosis is inflammation (8). Several studies have demonstrated that slightly elevated concentrations of C-reactive protein (CRP; a well-known acute-phase reactant named after its reactivity with the so-called C-polysaccharide of pneumococci) are predictive of coronary events in middle-aged and elderly men and women. However, the precise mechanism by which complement is involved in atherosclerosis is not known. In discussing a possible relationship between infections with pathogenic micro-organisms, MBL (an innate immune-defense plasma protein) deficiency and atherosclerosis, Madsen et al. (12) suggested the presence of unexpected non-infective mechanisms relevant to the development of atherosclerosis but could not conclusively exclude a relationship with other pathogens. The role of MBL in the immune system and the use of recombinant MBL in treating deficiencies in the immune system is well known (PCT International Patent Publication WO 00/70043). The present invention teaches how lipid metabolism, complement activation, atherogenic processes and immune responses are physiologically related.